MOLECULAR MECHANISM OF ACTION: Taxanes make microtubules ...edincell.bio.ed.ac.uk/.../files/ANTI-MITOTICS_Handouts.pdf · MOLECULAR MECHANISM OF ACTION: Taxanes make microtubules

telophase/cytokinesisanaphase

prophase prometaphase metaphase

Taxanes

(1) Targeting microtubules: TAXANES

MOLECULAR MECHANISM OF ACTION:

Taxanes make microtubules more stable

What do you think the consequences will

be for a dividing cell?

HOW TO KILL A MITOTIC CELL:

!dinCe"Mar Carmena

TAXANES (MICROTUBULE INHIBITORS)

EXAMPLE : TAXOL (PAXICLATEL)Isolated from the bark of the yew tree.

MOLECULAR MECHANISM OF ACTION

- Enhances stability of microtubules

- Mitosis blocks at the metaphase-anaphase transition.

Prolonged block results in cell death (apoptosis).

(Effect depends on drug concentration)

106 patients have been given taxol as part of their

chemotherapy regime world-wide.

ADVANTAGES

Very effective anti-tumor activity used in treatment of :

* ovarian cancer

* breast cancer

* non small cell lung cancer

DISADVANTAGES

-Severe adverse effects: neuropathies.

Microtubules are required for the transport of proteins and

vesicles along the axons of neurons.

- Development of resistance:

Tubulin mutations.

!dinCe"Mar Carmena



Vincas

(2) Targeting microtubules: VINCAS


Vincas make microtubules less stable




!dinCe"Mar Carmena

VINCAS (MICROTUBULE INHIBITORS)

EXAMPLE : Vincristine, vinblastine

Isolated from Madagascar periwinkle.


Inhibits polylmerization of microtubules

Blocks mitotic progression.

Prolonged block results in apoptosis (cell death).

ADVANTAGES

- Vinblastin used very successfully in combination

chemotherapy of Hodgkin’s lymphoma.

- With the introduction of vincristine, the survival rate for

children with leukemia jumped from 20 to 80 percent.

DISADVANTAGES

- Severe adverse effects: neuropathies. Microtubules

are required for the transport of proteins and vesicles

along axon fibers.

!dinCe"Mar Carmena



Monastrol

(3) Targeting proteins associated with microtubules

(Kinesins): MONASTROL


- Monastrol inhibits the activity of the protein Eg5.

- Eg5 is a kinesin (molecular motor). Its function is

to separate the poles of the spindle




!dinCe"Mar Carmena

KINESIN INHIBITORS

EXAMPLE : MONASTROL

Selected from a “library“ of small molecules.


- Inhibits the molecular motor Eg5, responsible for the

separation of centrosomes (spindle poles).

- Cells stop in mitosis with monopolar spindles and die by

apoptosis (cell death).

ADVANTAGES

- Only effect in dividing cells. No effect on interphase cells.

- No damage to neurons (no neuropathies).

DISADVANTAGES

- Development of resistance (Eg5 mutations).

!dinCe"Mar Carmena



BI 2536

Targeting proteins that control mitosis

(Kinases): BI 2536


- BI 2536 inhibits the activity of Plk1.

- Plk1 is a kinase (enzyme). It has multiple functions

in mitosis: control of entry into mitosis, formation of

bipolar spindle, attachment of the chromosomes to

the spindle and cytokinesis.



BI 2536


!dinCe"Mar Carmena

KINASE INHIBITORS

EXAMPLE : BI 2536



- Inhibits the enzyme Polo kinase (PLK1),

required for: entry in to mitosis, formation of the mitotic

spindle, attachment of the chromosomes to the spindle

and cytokinesis.

- Cells stop in mitosis and die by apoptosis (cell

death).

ADVANTAGES


- No damage to neurons (no neuropathies)

DISADVANTAGES

- Side effects: Bone marrow suppression.

Neutropenia

CLINICAL TRIALS: recurrent, metastatic solid tumors.

Prostate cancer, advanced pancreatic cancer, Breast

Cancer, Endometrial Cancer, Melanoma (Skin), Ovarian

Cancer.

!dinCe"Mar Carmena



MLN8237

Targeting proteins that control mitosis

(Kinases): MLN8237


- MLN8237 inhibits the activity of Aurora A. Aurora

A is a kinase (enzyme). It is required to control entry

into mitosis and formation of bipolar spindle.

What do you think the consequences

will be for a dividing cell?


!dinCe"Mar Carmena

KINASE INHIBITORS

EXAMPLE : MLN8237



- Inhibits the enzyme Aurora kinase A, required

for: entry in to mitosis, formation of the mitotic spindle,

- Cells get delayed in mitosis with monopolar

spindles; they eventually divide aberrantly. Cell death.

ADVANTAGES


-No damage to neurons (no neuropathies)

DISADVANTAGES


Neutropenia

CLINICAL TRIALS:Advanced solid tumors

!dinCe"Mar Carmena



(5) Targeting proteins that control mitosis

(Kinases): ZM447439


- ZM447439 inhibits the activity of Aurora B.

- Aurora B is a kinase (enzyme). It is required to

control attachment of the chromosomes to the

spindle and cytokinesis.



ZM447439


!dinCe"Mar Carmena

KINASE INHIBITORS

EXAMPLE : ZM447439



- Inhibits the enzyme Aurora kinase B. Aurora B

is required for multiple processes in mitosis: attachment of

the chromosomes to the mitotic spindle and cytokinesis.

- Cells get delayed in mitosis and fail cytokinesis,

generating polyploid cells. Cell death.

ADVANTAGES


-No damage to neurons (no neuropathies)

DISADVANTAGES


Neutropenia

CLINICAL TRIALS: ZM447439 is not used presently in

the clinic. Other Aurora B inhibitors are in clinical trials.

!dinCe"Mar Carmena

Documents

MOLECULAR MECHANISM OF ACTION: Taxanes make microtubules ...edincell.bio.ed.ac.uk/.../files/ANTI-MITOTICS_Handouts.pdf · MOLECULAR MECHANISM OF ACTION: Taxanes make microtubules